Search

Background: Faltering postnatal growth in preterm babies is associated with adverse neurodevelopment. However, which growth reference is most helpful for predicting neurodevelopment is unknown. We examined associations between faltering growth and developmental delay in extremely low birthweight (ELBW) infants., Methods: We categorized faltering growth (z-score decrease ≥0.8 for weight/length, >1 for head circumference) between birth, 4 weeks, 36 weeks' postmenstrual age and 2 years' corrected age using fetal (Fenton, UK-WHO and Olsen) and healthy preterm (INTERGROWTH-21st) references. Associations between faltering growth and developmental delay were examined using binary logistic regression and area under the receiver operating curve (AUC)., Results: In 327 infants, Olsen charts identified the highest prevalence of faltering growth (weight 37%, length 63%, head 45%). Agreement in classification was higher amongst fetal references (kappa coefficient, ĸ = 0.46-0.94) than between INTERGROWTH-21st and fetal references (ĸ = 0.10-0.81). Faltering growth in all measures between 4-36 weeks (odds ratio, OR 2.0-4.7) compared with other time intervals (OR 1.7-2.7) were more strongly associated with developmental delay, particularly motor delay (OR 2.0-4.7). All growth references were poorly predictive of developmental delay at 2 years (AUC ≤ 0.62)., Conclusions: Faltering postnatal growth in ELBW infants is associated with, but is poorly predictive of, developmental delay at 2 years., Impact: In babies born preterm, different growth references result in wide variation in categorization of faltering postnatal growth. Faltering growth in weight, length, and head circumference from 4 weeks to 36 weeks' postmenstrual age are associated with developmental delay at 2 years' corrected age, particularly motor delay. However, postnatal growth is a poor predictor of later developmental delay in extremely low birthweight infants irrespective of the growth reference used., (© 2024. The Author(s).)

Background: Appropriate protein intake is crucial for growth and development in children born preterm. We assessed the effects of high (HP) versus low protein (LP) intake on neurodevelopment, growth, and biochemical anomalies in these children., Methods: Randomised and quasi-randomised trials providing protein to children born preterm (<37 completed weeks of gestation) were searched following PRISMA guideline in three databases and four registers (PROSPERO registration CRD42022325659). Random-effects model was used for assessing the effects of HP (≥3.5 g/kg/d) vs. LP (<3.5 g/kg/d)., Results: Data from forty-four studies (n = 5338) showed HP might slightly reduce the chance of survival without neurodisability at ≥12 months (four studies, 1109 children, relative risk [RR] 0.95 [95% CI 0.90, 1.01]; P = 0.13; low certainty evidence) and might increase risk of cognitive impairment at toddler age (two studies; 436 children; RR 1.36 [0.89, 2.09]; P = 0.16; low certainty evidence). At discharge or 36 weeks, HP intake might result in higher weight and greater head circumference z-scores. HP intake probably increased the risk of hypophosphatemia, hypercalcemia, refeeding syndrome and high blood urea, but reduced risk of hyperglycaemia., Conclusions: HP intake for children born preterm may be harmful for neonatal metabolism and later neurodisability and has few short-term benefits for growth., Impact Statement: Planned high protein intake after birth for infants born preterm might be harmful for survival, neurodisability and metabolism during infancy and did not improve growth after the neonatal period. Protein intake ≥3.5 g/kg/d should not be recommended for children born preterm., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

We aimed to investigate whether gestation at birth, birth weight, and head circumference at birth are still associated with brain volume and white matter microstructure at 9-10 years in children born late-preterm and at term. One hundred and eleven children born at ≥ 36 weeks gestation from the CHYLD Study cohort underwent brain magnetic resonance imaging at 9 to 10 years. Images were analysed using FreeSurfer for volumetric data and tract-based spatial statistics for diffusion data. Of the cohort, 101 children were included for volumetric analysis [boys, 49(49%); median age, 9.5 (range: 8.9-12.4) years]. Shorter gestation at birth, lower birthweight, and smaller birth head circumference were associated with smaller brain volumes at 9 to 10 years, both globally and regionally. Amongst the perinatal factors studied, head circumference at birth was the strongest predictor of later brain volumes. Gestation at birth and absolute birthweight were not associated with diffusion metrics of white matter skeleton. However, lower birthweight z-score was associated with higher fractional anisotropy and lower radial diffusivity. Our findings suggest that even in children born late preterm and at term, growth before birth and timing of birth are still associated with brain development in mid-childhood., (© 2023. The Author(s).)

Exposure to low levels of nitrate in drinking water may have adverse reproductive effects. We reviewed evidence about the association between nitrate in drinking water and adverse reproductive outcomes published to November 2022. Randomized trials, cohort or case-control studies published in English that reported the relationship between nitrate intake from drinking water and the risk of perinatal outcomes were included. Random-effect models were used to pool data. Three cohort studies showed nitrate in drinking water is associated with an increased risk of preterm birth (odds ratio for 1 mg/L NO 3 -N increased (OR 1 ) = 1.01, 95% CI 1.00, 1.01, I 2  = 23.9%, 5,014,487 participants; comparing the highest versus the lowest nitrate exposure groups pooled OR (OR p ) = 1.05, 95% CI 1.01, 1.10, I 2  = 0%, 4,152,348 participants). Case-control studies showed nitrate in drinking water may be associated with the increased risk of neural tube defects OR 1  = 1.06, 95% CI 1.02, 1.10; 2 studies, 2196 participants; I 2  = 0%; and OR p  = 1.51, 95% CI 1.12, 2.05; 3 studies, 1501 participants; I 2  = 0%). The evidence for an association between nitrate in drinking water and risk of small for gestational age infants, any birth defects, or any congenital heart defects was inconsistent. Increased nitrate in drinking water may be associated with an increased risk of preterm birth and some specific congenital anomalies. These findings warrant regular review as new evidence becomes available., (© 2023. The Author(s).)

Background: Volatile compounds in breastmilk (BM) likely influence flavor learning and, through the cephalic phase response, metabolism, and digestion. Little is known about the volatile compounds present in preterm BM. We investigated whether maternal or infant characteristics are associated with the profile of volatile compounds in preterm BM., Methods: Using solid-phase microextraction coupled with gas chromatography/mass spectrometry, we analyzed volatile compounds in 400 BM samples collected from 170 mothers of preterm infants., Results: Forty volatile compounds were detected, mostly fatty acids and their esters (FA and FAe), volatile organic compounds (VOCs), aldehydes, terpenoids, alcohols, and ketones. The relative concentration of most FA and FAe increased with advancing lactation and were lower in BM of most socially deprived mothers and those with gestational diabetes (p < 0.05), but medium-chain FAs were higher in colostrum compared to transitional BM (p < 0.001). Infant sex, gestational age, and size at birth were not associated with the profile of volatile compounds in preterm BM., Conclusions: Sensory-active volatile FA and FAe are the major contributors to the smell of preterm BM. The associations between lactation stage, maternal characteristics, and volatile compounds, and whether differences in volatile compounds may affect feeding behavior or metabolism, requires further research., Impact: Sensory-active volatile FAs are major contributors to the smell of preterm BM and are influenced by the lactation stage and maternal characteristics. Longitudinal analysis of volatile compounds in preterm BM found that FAs increased with advancing lactation. Colostrum had a higher concentration of medium-chain FAs compared to transitional BM and the concentration of these is associated with socioeconomic status, gestational diabetes, and ethnicity., (© 2021. The Author(s).)

Background: We performed a case-control study to characterise infants with "prolonged transitional hypoglycaemia"., Methods: Cases were born ≥36 weeks' gestation; had ≥1 hypoglycaemic episode <72 h and ≥72 h; received ongoing treatment for hypoglycaemia ≥72 h; and were without congenital disorders or acute illness. Cases were compared to controls born ≥36 weeks' with brief transitional hypoglycaemia, resolving <72 h., Results: 39/471 infants screened met case definition: 71.8% were male, 61.5% were small-for-gestational-age (SGA), and most were admitted <6 h. Compared to controls (N = 75), key risk factors for prolonged transitional hypoglycaemia were SGA (OR = 6.4, 95%CI 2.7-15.1), severe/recurrent hypoglycaemia <24 h (OR = 16.7, 95%CI 4.5-16.1), intravenous glucose bolus <24 h (OR = 26.6, 95%CI 9.4-75.1) and maximum glucose delivery rate <48 h of ≥8 mg/kg/min (OR = 25.5, 95%CI 7.7-84.1)., Conclusions: Infants with prolonged transitional hypoglycaemia are predominantly male, SGA and have early severe/recurrent hypoglycaemia requiring glucose boluses and high glucose delivery rates in the first 24-48 h.

Nutritional intake can promote early neonatal brain development in very preterm born neonates (< 32 weeks' gestation). In a group of 7-year-old very preterm born children followed since birth, we examined whether early nutrient intake in the first weeks of life would be associated with long-term brain function and neurocognitive skills at school age. Children underwent resting-state functional MRI (fMRI), intelligence testing (Wechsler Intelligence Scale for Children, 5th Ed) and visual-motor processing (Beery-Buktenica, 5th Ed) at 7 years. Relationships were assessed between neonatal macronutrient intakes, functional connectivity strength between thalamic and default mode networks (DMN), and neuro-cognitive function using multivariable regression. Greater functional connectivity strength between thalamic networks and DMN was associated with greater intake of protein in the first week (β = 0.17; 95% CI 0.11, 0.23, p < 0.001) but lower intakes of fat (β = - 0.06; 95% CI - 0.09, - 0.02, p = 0.001) and carbohydrates (β = - 0.03; 95% CI - 0.04, - 0.01, p = 0.003). Connectivity strength was also associated with protein intake during the first month (β = 0.22; 95% CI 0.06, 0.37, p = 0.006). Importantly, greater thalamic-DMN connectivity strength was associated with higher processing speed indices (β = 26.9; 95% CI 4.21, 49.49, p = 0.02) and visual processing scores (β = 9.03; 95% CI 2.27, 15.79, p = 0.009). Optimizing early protein intake may contribute to promoting long-term brain health in preterm-born children.

Early dietary exposure may influence infant appetitive feeding behaviour, and therefore their later health. Maternal diabetes in pregnancy is associated with an increased risk of obesity in the offspring. We, therefore, examined third-trimester dietary patterns of women with gestational diabetes, their offspring's appetitive feeding behaviour at 6 months of age, and relationships between these. We used data from a prospective cohort of women with gestational diabetes and assessed maternal dietary patterns at 36 weeks' gestation using principal component analysis; infant appetitive feeding behaviour at 6 months of age using the Baby Eating Behaviour Questionnaire; and relationships between these using general linear modelling and chi-square tests. In 325 mother-infant dyads, we identified three distinct maternal dietary patterns: 'Junk,' 'Mixed,' and 'Health-conscious.' The maternal 'Health-conscious' pattern was inversely associated with 'enjoyment of food' in their sons (β - 0.24, 95% CI - 0.36 to - 0.11, p = 0.0003), but not daughters (β - 0.02, 95% CI - 0.12 to 0.08, p = 0.70), and was positively associated with 'slowness in eating,' (β 0.13, 95% CI 0.02 to 0.24, p = 0.01). Third-trimester dietary patterns in women with gestational diabetes may have sex-specific effects on infant appetitive feeding behaviour at 6 months of age.

Background: Little is known about normative ammonia concentrations in extremely low birthweight (ELBW) babies and whether these vary with birth characteristics. We aimed to determine ammonia concentrations in ELBW babies in the first week after birth and relationships with neonatal characteristics and protein intake., Methods: Arterial blood samples for the measurement of plasma ammonia concentration were collected within 7 days of birth from ProVIDe trial participants in six New Zealand neonatal intensive care units., Results: Three hundred and twenty-two babies were included. Median (range) gestational age was 25.7 (22.7-31.6) weeks. Median (interquartile range (IQR)) ammonia concentration was 102 (80-131) µg/dL. There were no statistically significant associations between ammonia concentrations and birthweight or sex. Ammonia concentrations were weakly correlated with mean total (Spearman's r s  = 0.11, P = 0.047) and intravenous (r s  = 0.13, P = 0.02) protein intake from birth, gestational age at birth (r s  = -0.13, P = 0.02) and postnatal age (r s  = -0.13, P = 0.02)., Conclusions: Plasma ammonia concentrations in ELBW babies are similar to those of larger and more mature babies and only weakly correlated with protein intake. Currently, recommended thresholds for investigation of hyperammonaemia are appropriate for ELBW babies. Protein intake should not be limited by concerns about potential hyperammonaemia.

Objective: To compare rates of small- and large-for-gestational age (SGA and LGA) neonates using four different weight centiles, and to relate these classifications to neonatal morbidity., Study Design: Neonates born at 33-40 weeks' gestation in a multiethnic population were classified as SGA or LGA by population reference (Fenton), population standard (INTERGROWTH), fetal growth curves (WHO), and customized (GROW) centiles. Likelihood of composite morbidity was determined compared with a common appropriate-for-gestational age referent group., Result: Among 45,505 neonates, SGA and LGA rates varied up to threefold by different centiles. Those most likely to develop neonatal morbidity were SGA or LGA on both the population reference and an alternative centile. Customized centiles identified over twice as many at-risk SGA neonates., Conclusions: Customized centiles were most useful in identifying neonates at increased risk of morbidity, and those that were small on both customized and population reference centiles were at the highest risk.

Background: Although early nutrition is associated with neurodevelopmental outcome at 2 years' corrected age in children born very preterm, it is not clear if these associations are different in girls and boys., Methods: Retrospective cohort study of infants born <30 weeks' gestational age or <1500 g birth weight in Auckland, NZ. Macronutrient, energy and fluid volumes per kg per day were calculated from daily nutritional intakes and averaged over days 1-7 (week 1) and 1-28 (month 1). Primary outcome was survival without neurodevelopmental impairment at 2 years corrected age., Results: More girls (215/478) survived without neurodevelopmental impairment at 2 years (82% vs. 72%, P = 0.02). Overall, survival without neurodevelopmental impairment was positively associated with more energy, fat, and enteral feeds in week 1, and more energy and enteral feeds in month 1 (P = 0.005-0.03), but all with sex interactions (P = 0.008-0.02). In girls but not boys, survival without neurodevelopmental impairment was positively associated with week 1 total intakes of fat (OR(95% CI) for highest vs. lowest intake quartile 62.6(6.6-1618.1), P < 0.001), energy (22.9(2.6-542.0), P = 0.03) and enteral feeds (1.9 × 10 9 (9.5-not estimable), P < 0.001)., Conclusions: Higher early fat and enteral feed intakes are associated with improved outcome in girls, but not boys. Future research should determine sex-specific neonatal nutritional requirements.

Early macronutrient supplementation in preterm and/or small-for-gestational-age (SGA) infants may improve growth but have detrimental effects on later cardio-metabolic health which may be sex-specific. We systematically reviewed the long-term effects of early macronutrient supplementation in preterm and SGA animals and whether these differ by sex. Using Cochrane Neonatal and SYRCLE methodologies we included random or quasi-random studies that allocated non-human mammals to macronutrient supplements or no supplements between birth and weaning and assessed post-weaning outcomes. We used random-effects models to calculate standardized mean differences (SMD) with 95% confidence intervals (CIs). Six studies provided low to very-low-quality evidence that macronutrient supplementation increased weight in juvenile rats (SMD; 95% CI: 2.13; 1.00, 3.25; 1 study, n = 24), increased leptin concentrations in older adults (1.31; 0.12, 2.51; 1 study, n = 14 male rats), but decreased leptin concentrations in young adults (-1.13; -2.21, -0.05; 1 study, n = 16 female rats) and improved spatial learning and memory (qualitative data; 1 study). There was no evidence of sex-specific effects and no overall effect on length, serum lipids, body composition, HOMA-IR, or blood pressure. Macronutrient supplements may affect later growth, metabolism, and neurodevelopment of preterm and SGA animals, but evidence is limited and low quality.

Higher and unstable glucose concentrations in the first 48 hours in neonates at risk of hypoglycaemia have been associated with neurosensory impairment. It is unclear what defines and contributes to instability. This was a prospective study of term and late preterm babies (N = 139) born at risk of neonatal hypoglycaemia who had interstitial glucose (IG) monitoring and ≥1 hypoglycaemic episode <48 hours after birth (blood glucose concentration <2.6 mmol/l [<47 mg/dl]). For 6-hour epochs after each hypoglycaemic episode, masked IG parameters (time to reach maximum IG concentration [hours]; range, average, maximum and minimum IG concentrations; proportion of IG measurements outside the central band of 3-4 mmol/l [54-72 md/dl]; and total duration [hours] of IG concentrations <2.6 mmol/l) were analysed in tertiles and related to: (i) glycaemic instability in the first 48 hours (defined as the proportion of blood glucose concentrations outside the central band in the first 48 hours); (ii) risk factors and treatment for each episode; and (iii) risk of neurosensory impairment at 4.5 years, or at 2 years if a child was not seen at 4.5 years. Glycaemic instability in the first 48 hours was related to IG instability after hypoglycaemia. Risk factors for hypoglycaemia were not related to IG parameters. Treatment with intravenous dextrose was associated with higher IG maximum and range, and lower minimum compared to treatment with dextrose gel plus breast milk, breast milk alone or formula alone. The risk of neurosensory impairment was increased with both shorter and longer time to reach maximum epoch IG (P = 0.04; lower tertile [0.4-2.2 hours] vs middle [2.3-4.2 hours] OR 3.10 [95% CI 1.03; 9.38]; higher tertile [4.3-6.0 hours] vs middle OR 3.07; [95% CI 1.01; 9.24]). Glycaemic response to hypoglycaemia contributes to overall glycaemic instability in newborns and is influenced by treatment. Slow or rapid recovery of hypoglycaemia appears to be associated with neurosensory impairment.

Background: The nutritional plane and composition during fetal life can impact upon growth and epigenetic regulation of genes affecting pancreatic β-cell development and function. However, it is not clear whether β-cell development can be altered by nutritional factors or growth rate after birth. We therefore investigated the effect of neonatal nutritional supplements on growth, glucose tolerance, and pancreatic development in lambs., Methods: Newborn lambs were randomized to daily nutritional supplements, calculated to increase macronutrient intake to a similar degree as human breast milk fortifier, or an equivalent volume of water, for 2 wk while continuing to suckle ewe milk. Intravenous glucose tolerance test (IVGTT) was performed at 4 mo of age, and pancreata collected for molecular analysis., Results: Supplemented lambs had slower weight gain than controls. In supplemented lambs, insulin response to IVGTT was increased in males but decreased in females, compared to same sex controls, and was unrelated to growth rate. mRNA expression of key genes in β-cell development showed sexually dimorphic effects. Epigenetic change occurred in the promotor region of PDX1 gene with decreased suppression and increased activation marks in supplemented lambs of both sexes., Conclusion: Nutritional interventions in early life have long-term, sex-specific effects on pancreatic function.

Periconceptional undernutrition and twin conception alter intrauterine growth and metabolism and are associated with later adverse metabolic outcomes. The contribution of postnatal growth to these outcomes is less well defined. We investigated whether maternal periconceptional undernutrition or twin conception altered postnatal growth regulation in ways that could lead to metabolic disease. Single and twin offspring of ewes undernourished (UN) from 61 d before until 30 d after mating, fed to achieve and maintain 10-15% weight loss (UN), were compared with offspring of maintenance-fed controls (N). At 2 h and 1, 6, and 12 wk after birth, lambs were weighed and plasma hormone and metabolite concentrations analyzed. Milk intake, measured by deuterium oxide dilution, was inversely related to birth weight only in N singles, although twins had the greatest postnatal growth velocity. Positive associations were seen between milk intake, growth velocity, and leptin concentrations in N, but not UN, offspring. We conclude that periconceptional undernutrition alters the relationships between regulators of postnatal growth, including nutrient intake and key hormonal axes, in both singles and twins without affecting size at birth or postnatal growth velocity. Dissociation of growth from its key regulators is one possible mechanism underlying adverse metabolic outcomes after periconceptional undernutrition.

We have used aminoterminal pro C-type natriuretic peptide (NTproCNP)--a stable marker of CNP secretion--to study the effect of cortisol on CNP secretion and fetal growth. In ovine pregnancy, maternal plasma NTproCNP (largely sourced from the placenta) increases at the end of the first trimester and then decreases abruptly preterm during the phase of fetal surge in cortisol secretion. Postulating that increases in cortisol, as occurs in the fetal or maternal circulation in late pregnancy, will reduce CNP secretion, we studied the fetal and maternal responses in NTproCNP to sustained low-dose infusions of cortisol (1.2 mg/d/kg for 11 d) delivered to the fetus from d 117 gestation. Fetal plasma NTproCNP was progressively reduced during fetal cortisol infusions, whereas fetal girth growth was unchanged. In contrast, maternal NTproCNP was unaffected by cortisol. We conclude that fetal but not placental tissue production of CNP is reduced by small increments in fetal cortisol. Failure to reduce maternal NTproCNP may relate to the continuing presence of the placental barrier to cortisol at this stage of pregnancy.

Periconceptional undernutrition alters fetal growth and development. However, there are no data on separate effects of undernutrition before and after conception and few on underlying mechanisms. We determined the effects of mild periconceptional undernutrition on late gestation fetal growth, glucose-insulin axis, and maternal and fetal hypothalamic-pituitary-adrenal axes. Ewes were undernourished for 60 d before conception, 30 d after, or both, compared with well-nourished controls. Undernutrition before conception resulted in smaller, slower-growing fetuses with relatively larger placentae. Ewes that gained weight before, but lost weight after mating, or vice versa, had the smallest fetuses. Fetuses of ewes undernourished only before conception grew more slowly following instrumentation, and fetuses in both preconception undernutrition groups slowed their growth with a maternal fast. The fetal glucose-insulin axes and maternal and fetal hypothalamic-pituitary-adrenal axis were not different among groups. Maternal undernutrition at different periods around conception has different effects on fetal growth trajectory that are not reflected in size in late gestation. Preconceptional undernutrition alone alters fetal growth responses to late gestation stressors, suggesting that maternal nutrition is important at both times, and that fetal effects are neither due solely to substrate limitation, nor to excess fetal glucocorticoid exposure at the time of undernutrition.

Maternal undernutrition throughout pregnancy can have long-term effects on the health of adult offspring. Undernutrition around the time of conception alters growth, metabolism, and endocrinology of the sheep fetus, but the impact on offspring after birth is largely unknown. We determined the effect of maternal periconceptional undernutrition in sheep on glucose tolerance in the offspring before and after puberty. Undernourished (UN) ewes were fed individually to maintain weight loss of 10-15% bodyweight from 61 d before until 30 d after mating. Offspring (24 UN, 30 control) underwent an i.v. glucose tolerance test at 4 and 10 mo of age. Glucose tolerance was similar in both groups at 4 mo. Insulin area under the curve increased by 33% between 4 and 10 mo (101 +/- 8 versus 154 +/- 12 ng x min x mL(-1), p < 0.0001). At 10 mo, UN offspring had a 10% greater glucose area under the curve than controls (809 +/- 22 versus 712 +/- 20 mM x min, p < 0.01), a reduced first phase insulin response (p = 0.003) which was particularly apparent in females and in singletons, and a decreased insulin:glucose ratio (p = 0.01). We conclude that maternal undernutrition around the time of conception results in impaired glucose tolerance in postpubertal offspring.

Low cerebral blood flow in preterm infants has been associated with discontinuous electroencephalography (EEG) activity that in turn has been associated with poor long-term prognosis. We examined the relationships between echocardiographic measurements of blood flow, blood pressure (BP), and quantitative EEG data as surrogate markers of cerebral perfusion and function with 112 sets of paired data obtained over the first 48 h after birth in 40 preterm infants (24-30 wk of gestation, 510-1900 g at delivery). Echocardiographic measurements of right ventricular output (RVO) and superior vena caval (SVC) flow were performed serially. BP recordings were obtained from invasive monitoring or oscillometry. Modified cotside EEGs were analyzed for quantitative amplitude and continuity measurements. RVO 12 h after birth was related to both EEG amplitude at 12 and 24 h and continuity at 24 h. Mean systemic arterial pressure (MAP) at 12 and 24 h was related to continuity at 12 and 24 h after birth. Multiple regression analyses revealed that RVO at 12 h was related to median EEG amplitude at 24 h and diastolic BP at 24 h was related to simultaneous EEG continuity. In addition, at 12 h, infants in the lowest quartile for RVO measurements (<282 mL/kg/min) had lower EEG amplitude and those in the lowest quartile for MAP measurements (<31 mm Hg) had lower EEG continuity. These results suggest a relationship between indirect measurements of cerebral perfusion and cerebral function soon after birth in preterm infants.

Protein metabolism may be perturbed in intrauterine growth restriction (IUGR). Arginine is indispensable for growth and nitrogen balance in young mammals. Fetuses with IUGR therefore may benefit from arginine supplementation. The purpose of this study was to determine 1) the effects of IUGR on protein metabolism in the ovine fetus and 2) the effects of arginine or mixed amino acid (AA) infusion on protein metabolism in these fetuses. Pregnant ewes and their fetuses were catheterized at 110 d gestation and randomly assigned to control or IUGR groups. IUGR was induced by repetitive placental embolization. Parameters of fetal protein metabolism were determined from [ring-(2)H(5)]phenylalanine kinetics at baseline and in response to a 4-h infusion of either arginine or an isonitrogenous AA mixture. There were no differences in protein metabolism between control and IUGR groups either at baseline or in response to arginine or AA treatment. Both arginine and AA infusion increased fetal protein accretion in both groups. Arginine did this by decreasing protein turnover, synthesis, and breakdown. AAs increased protein turnover and synthesis while decreasing protein breakdown. AA infusion resulted in a significantly higher increase in protein accretion than arginine infusion. Thus, in the ovine fetus, placental embolization has no clear effect on protein metabolism. Arginine and AAs both stimulate protein accretion but do so in distinctly different ways. Mixed AA infusion has a greater effect on protein accretion than arginine alone and therefore may be a better strategy for stimulating fetal growth.

Maternal undernutrition during pregnancy can lead to impaired metabolic regulation in postnatal offspring. The extent to which such abnormalities are determined in early gestation, and may already be present in fetal life, is unknown. We studied the effect of periconceptional undernutrition on fetal growth and metabolism in late gestation. Ewes were either well fed throughout pregnancy (N) or undernourished to reduce ewe weight by 15% from 61 d before until 30 d after mating (UN). At 121 d, one cohort of ewes and their singleton fetuses (N, n=10; UN, n=10) were fasted for 72 h, given 25 g of glucose i.v. over 8 h, and refed. Fetal and placental weights were not different at 131 d. UN ewes had higher glucose, amino nitrogen, and Hb concentrations than N ewes. UN fetuses had higher glucose and lactate, and lower amino nitrogen and O2 concentrations and pH. UN ewes had higher insulin and lower IGF-I concentrations, and UN ewes and fetuses had higher placental lactogen concentrations. A second cohort (N, n=8; UN, n=10) were studied until term. Chest girth increment was reduced in UN fetuses until delivery, but birth weights were not significantly reduced. These findings suggest that fetal growth, metabolic and endocrine status, and placental function in late gestation are influenced by maternal nutrition in the periconceptional period, independent of fetal size. Metabolic and endocrine adaptations in the mother may mediate some of these effects. Such adaptations may allow continued fetal growth and survival in the face of a potentially adverse nutritional environment.

Both small size at birth in humans and maternal undernutrition in experimental animals are associated with impaired glucose tolerance and increased blood pressure in the adult offspring. However it is not clear whether maternal undernutrition in late gestation can influence postnatal phenotype, and whether this might occur independent of size at birth. We severely undernourished pregnant ewes for 10 d (UN10) or 20 d (UN20) from 105 d gestation (term = 146 d) and studied the offspring in comparison to those born to ad libitum fed ewes (AL20). Glucose tolerance tests and blood pressure recordings were performed at 5 mo of age and repeated at 30 mo together with insulin tolerance tests and GH challenges. UN20 lambs were lighter at birth (UN20, 4.9 +/- 0.1 kg, n = 23; UN10, 5.3 +/- 0.1 kg, n = 26; AL20, 5.6 +/- 0.2 kg, n = 26) but not from weaning onward. Plasma glucose area under the curve at 5 mo and plasma insulin at 30 mo increased with current weight and decreased with increasing birth weight. Blood pressure also increased with current weight and decreased with increasing birth weight at 5 but not 30 mo. Plasma IGF-I concentrations increased with current weight at all ages and decreased with increasing birth weight at 30 mo. Plasma insulin response to GH challenge increased with current weight. Nutrition group was not related to any of the outcomes measured when birth weight and current weight were taken into account. These data suggest that size at birth is more closely related to processes that determine postnatal phenotype than is maternal nutrition in late gestation.

Large amounts of amniotic fluid (AF) are swallowed in late gestation. AF is the most accessible fetal compartment and provides a possible paraplacental route for the therapeutic administration of hormones and nutrients to the fetus. We therefore wished to investigate the fate of the predominant fetal growth factor, IGF-I, administered into AF of late-gestation ovine fetuses. Seven chronically catheterized fetuses at 124 d gestation had approximately 800 x 10(6) dpm of (125)I-IGF-I injected into the AF. AF and blood samples were withdrawn for up to 6 d. At 131 d gestation a postmortem examination was performed. All AF, blood, and tissue samples were counted. Selected samples of AF, blood, and gut contents underwent size-separation chromatography. (125)I-IGF-I was rapidly mixed in AF, with a significant difference in counts from different regions of the cavity persisting for only 3 h (p < 0.05). In vivo binding of (125)I-IGF-I in AF correlated highly with AF IGF binding protein 3 concentrations (r(2) = 0.93, p < 0.0001). In some animals, free (125)I-IGF-I persisted in AF and in plasma for the duration of the experiments. Chromatography of plasma samples demonstrated that intact (125)I-IGF-I was taken up from the fetal gut. Only fetal gut and thyroid contained appreciable counts at postmortem examination. Gut contents had more counts than gut wall, and the number of counts in gut contents increased distally (p < 0.05 for colon contents versus other regions). We conclude that there is sustained delivery of (125)I-IGF-I from the AF to the gut and systemic circulation of the ovine fetus after a single intraamniotic injection.